Preservative-free single dose inhaler systems

CROSS-REFERENCES TO RELATED APPLICATIONS

0001This application is a continuation of U.S. patent application Ser. No. 14/039,254, filed on Sep. 27, 2013, now U.S. Pat. No. 9,004,061, which is a continuation of U.S. patent application Ser. No. 13/004,662, filed on Jan. 11, 2011, now U.S. Pat. No. 8,950,394, which claims priority from U.S. Provisional Application No. 61/335,769, filed on Jan. 12, 2010, which are herein incorporated by reference.

FIELD OF THE INVENTION

0002This invention relates generally to a single dose inhaler and insulin formation containers. The inhaler dispenses aerosolized pharmaceutical agents for local or systemic inhalation drug delivery to the lungs. The invention is particularly, but not exclusively, useful for delivery of preservative free doses of insulin for treating type I and/or type II diabetic patients.

BACKGROUND OF THE INVENTION

0003Various types of inhalers exist for aerosolizing liquids. For example, U.S. Pat. No. 5,586,550, incorporated herein by reference, describes an inhaler which comprises a dispensing apparatus in which a membrane with tapered apertures is vibrated such that liquid in contact with a rear face of the membrane is dispensed from a front face of the membrane as an aerosol.

0004While effective at nebulizing liquids, such inhalers may not be particularly suited for certain applications, such as aerosolizing unit doses of insulin for pulmonary delivery.

0005Hence, the invention provides inhalers for delivering doses in a repeatable and predictable fashion. As described hereinafter, the inhalers of the invention may find particular use in aerosolizing liquid insulin for pulmonary delivery.

BRIEF SUMMARY OF THE INVENTION

0006The invention provides various aerosolization systems, including containers for supplying liquid to inhalers, as well as methods for their use. In one exemplary embodiment, the invention provides an aerosolization system that comprises a squeezable container having a resilient container body. The container is configured to deliver a unit dosage of a liquid when squeezed a single time.

0007The system further includes an aerosolizer that comprises a housing defining a mouthpiece, and an aerosol generator disposed in the housing. The aerosol generator comprises a vibratable membrane having a front face and a rear face, and a vibratable element used to vibrate the membrane. Further, the housing includes an opening that is adapted to receive a unit dosage of the liquid from the container. The opening provides a liquid path to the rear face of the vibratable membrane.

0008In one aspect, the aerosolizer includes a hollow needle that is configured to pierce the squeezable container and to supply the liquid to the rear face of the vibratable membrane. Also, the squeezable container may comprise a blister containing a single unit dosage. For example, the blister may comprise a blow-fill-seal container that contains a preservative free solution. The blister may further comprise a squeezable body containing the solution, a twist off top and a tab adapted to display information about the solution.

0009In a further aspect, the single unit dosage has a concentration in the range from about 200 insulin units (“IU”)/ml to about 800 IU/ml.

0010In another embodiment, the container comprises a bottle containing of volume of the liquid. In one aspect, the bottle may include a metering valve that permits dispensing of a discrete droplet of the liquid each time the bottle is squeezed. In other cases, the size of the droplet may be controlled based at least in part on the diameter of the tip of the bottle and the viscosity of the liquid.

0011The invention further provides another aerosolization system that comprises a container in the form of an ampoule containing a capillary that holds a single unit dosage of a liquid. The system also includes an aerosolizer comprising a housing defining a mouthpiece, and an aerosol generator disposed in the housing. The aerosol generator comprises a vibratable membrane having a front face and a rear face, and a vibratable element used to vibrate the membrane. Also, the housing includes an opening that is adapted to receive a unit dosage of the liquid from the container. Further, the opening provides a liquid path to the rear face of the vibratable membrane.

0012In one particular aspect, the ampoule further comprises a snap-off top and a snap-off bottom. The capillary is sized such that surface tension in the capillary prevents leakage of the liquid after removal of the top but prior to removal of the bottom.

0013A further embodiment of the invention provides an aerosolization system having a container comprising a container body that holds a supply of liquid, and a plunger device that is movable to dispense a single unit dosage of a liquid from the container upon operation of the plunger device a set distance. An aerosolizer comprises a housing defining a mouthpiece, and an aerosol generator disposed in the housing. The aerosol generator comprises a vibratable membrane having a front face and a rear face, and a vibratable element used to vibrate the membrane. Further, the housing includes an opening that is adapted to receive a unit dosage of the liquid from the container. The opening provides a liquid path to the rear face of the vibratable membrane.

0014In one aspect, the container further includes a metering device that is rotated to control movement of the plunger in order to set a single unit dosage amount.

BRIEF DESCRIPTION OF THE DRAWINGS

<figref idref="DRAWINGS">FIG. 1</figref> is a perspective, partial cut-away view of one embodiment of a dispensing apparatus and squeezable container according to the invention.

<figref idref="DRAWINGS">FIG. 2</figref> is a more detailed view of the dispensing apparatus and container of <figref idref="DRAWINGS">FIG. 1</figref>.

<figref idref="DRAWINGS">FIG. 3</figref> is illustrates the dispensing device of <figref idref="DRAWINGS">FIG. 1</figref>, showing a more detailed view of a seat for holding the container and a needle for supplying dispensed liquid to an aerosol generator.

<figref idref="DRAWINGS">FIG. 4</figref> is a perspective view of another embodiment of a dispensing apparatus and an a squeezable bottle according to the invention.

<figref idref="DRAWINGS">FIG. 4A</figref> is a cross sectional schematic view of a portion of the bottle of <figref idref="DRAWINGS">FIG. 4</figref> in a closed position.

<figref idref="DRAWINGS">FIG. 4B</figref> is a cross sectional schematic view of a portion of the bottle of <figref idref="DRAWINGS">FIG. 4</figref> in an open position.

<figref idref="DRAWINGS">FIG. 5</figref> illustrates another embodiment of a container for dispensing a unit volume of a liquid according to the invention.

<figref idref="DRAWINGS">FIG. 6</figref> illustrates the container of <figref idref="DRAWINGS">FIG. 5</figref> when dispensing a unit volume of liquid into the dispensing apparatus of <figref idref="DRAWINGS">FIG. 4</figref>.

<figref idref="DRAWINGS">FIG. 7</figref> illustrates an embodiment of an ampoule for dispensing a unit volume of a liquid according to the invention.

<figref idref="DRAWINGS">FIG. 8</figref> illustrates the ampoule of <figref idref="DRAWINGS">FIG. 7</figref> with an end removed.

<figref idref="DRAWINGS">FIG. 9</figref> illustrates the ampoule of <figref idref="DRAWINGS">FIG. 8</figref> with the top end also removed and being deposited into a dispensing apparatus.

<figref idref="DRAWINGS">FIG. 10</figref> illustrates another embodiment of a container for dispensing a unit volume of a liquid into the dispensing apparatus of <figref idref="DRAWINGS">FIG. 4</figref>.

DETAILED DESCRIPTION OF THE INVENTION

0027Certain aspects of the invention describe an aerosolizing apparatus comprising a housing defining a dispensing outlet, a vibratable membrane having a front face exposed at the outlet and a rear face for receiving a liquid to be dispensed, and a vibrating mechanism connected to the housing and operable to vibrate the membrane to dispense aerosol of the liquid through the membrane. A liquid delivery system is used to deliver a metered quantity of the liquid from to the rear face of the membrane. In this way, a metered quantity of liquid is dispensable at the outlet by operating the vibrating mechanism for an operating period sufficient to completely aerosolize the metered quantity of the rear face.

0028An advantage of such an apparatus is that it facilitates the dispensing of substantially all of the liquid coming into contact with the rear face of the membrane as a single dose, especially when the metered dose is relatively small in volume. By dispensing the entire dose, the membrane is essentially free of liquid from one dose to the next. In this way, it is thereby possible to avoid contact between liquid and ambient air during periods of non-use between successive uses. For pharmaceutical preparations this is particularly important since it may obviate the need for the use of preservatives in the liquid and avoids evaporative losses. For example, various preservative free insulin formulations that may be used include those described in copending U.S. application Ser. No. 13/004,662, entitled “Preservative Free Insulin Formulations and Systems and Methods for Aerosolizing” and filed on the same date as the present application, previously incorporated by reference.

0029The liquid supply system in one embodiment may comprise a deformable thin-wall blister which contains a pharmaceutical agent. The supply system further comprises a mechanical press configured to deform the thin-walled blister such that a single, preservative free unit dose is delivered. The press mechanism is provided with a dispensing station provided with a piercing needle operable to pierce the blister and release its content upon actuation.

0030In one aspect, the needle has two ends, with the first end protruding from the surface of the dispensing station and a second end extending to rear face of the aerosol generator. In use the blister is seated in the dispensing station and the press mechanism forces the blister toward the needle which pierces through the thin wall. In this way, the needle provides a conduit for moving the liquid from the blister to the rear face of the vibratable membrane. When the press mechanism is released the blister expands and returns to its natural position. This expansion creates a suction action which removes the liquid from the needle and prevents dry out and clogging.

0031In a further aspect, the blister has a bellows shaped geometry which can elastically expand and compress. The term elastically expand and compress includes when the blister is fully compressed the internal stresses are still within the elastic range of the material in use, thus, the blister can return to its natural position when the press mechanism is released. In one particular aspect, the pharmaceutical agent fills at least 80% the internal volume of the blister and more preferably more than 90% of the volume. This prevents movement of liquid which in some cases may cause aggregation of the composition.

0032Conveniently, the end of the needle may be positioned in close proximity to the rear face of the vibratable membrane. Further, the housing may define a duct communicating between an air inlet and an outlet port. The dispensing outlet is located in the duct intermediate the air inlet and the outlet port such that the front face of the membrane is exposed to air within the duct. The outlet port may be a mouthpiece for inhalation or an adapter for nasal use.

0033Such an arrangement is particularly useful in the administration of inhaled pharmaceutical liquid products where it is required that a fine aerosol of liquid be entrained in an inhaled air flow passing through the mouthpiece. One example of such a liquid is an insulin composition.

0034Referring now to <figref idref="DRAWINGS">FIG. 1</figref>, one embodiment of an inhaler will be described. <figref idref="DRAWINGS">FIG. 1</figref> illustrates a partially cut-away view of the single-dose-inhaler <b>100</b> and a unit dose blister <b>201</b> package for supplying a metered quantity of insulin to the inhaler. Inhaler <b>100</b> comprises two subassemblies <b>102</b> and <b>112</b>. The first subassembly <b>102</b> defines a compartment for the electronic circuitry and the batteries, and the second subassembly <b>112</b> defines a housing with a dispensing outlet <b>105</b> and contains a vibratable membrane aerosol generator <b>108</b> and a dispensing mechanism <b>104</b>. Aerosol generator <b>108</b> has a front face exposed at the outlet duct <b>111</b> and a rear face <b>109</b> contacted in use by liquid to be dispensed. Aerosol generator <b>108</b> is connected to the housing of subassembly <b>112</b> and is operable to dispense the active pharmaceutical agent as an aerosol through the mouthpiece <b>105</b>. Exemplary aerosol generators that may be used are also described in U.S. Pat. Nos. 5,164,740; 6,629,646; 6,926,208; 7,108,197; 5,938,117; 6,540,153; 6,540,154; 7,040,549; 6,921,020; 7,083,112; 7,628,339; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804; 7,174,888; 6,014,970; 6,205,999; 6,755,189; 6,427,682; 6,814,071; 7,066,398; 6,978,941; 7,100,600; 7,032,590; 7,195,011, incorporated herein by reference. These references describe exemplary aerosol generators, ways to manufacture such aerosol generators and ways to supply liquid to aerosol generators, and are incorporated by reference for at least these features. The aerosol generators may comprise vibratable membranes having tapered aperture with a size in the range from about 3 μm to about 8 μm, preferably from about 3 μm to about 6 μm, and in some cases around 4 μm. The membrane may be domed shaped and be vibrated by an annular piezoelectric element that circumscribes the apertures. The diameter of the membrane may be in the range from about 5 mm to about 8 mm. The membrane may also have a thickness in the range from about 50 microns to about 70 microns. Typically, the membrane will be vibrated at a frequency in the range from about 50 kHz to about 150 kHz.

0035Each time the dispensing system is operated it delivers a metered quantity of the liquid from the unit dose blister <b>201</b> to the rear face <b>109</b> of the aerosol generator. Hence, for each use a metered quantity of aerosolized pharmaceutical agent is dispensed at the mouthpiece outlet <b>105</b> by operation of the aerosol generator.

0036The blister <b>201</b> contains a predetermined volume of an active pharmaceutical agent to be dispensed. In one embodiment the blister <b>201</b> contains about 80 to about 120 micro-liters of insulin. The lower limit is typically at least about 15 micro-liters and the upper limit is typically about 1,000 micro-liters to about 2,000 micro-liters. One particularly useful range is about 80 micro-liters to about 120 micro-liters in a concentration of about 100 insulin units/ml or greater, and more preferably between about 200-800 units/ml, and in some cases as high as 2,500 units/ml. Blister <b>201</b> is made of thin-walled deformable material. Due to sensitivity of insulin to mechanical agitation, the blister <b>201</b> is filled-up to nearly its entire volume. Specifically, more than 80% of the volume is filled with insulin.

0037Inhaler <b>100</b> further includes a dispensing station configured to dispense the content of the blister <b>201</b> to the aerosol generator <b>108</b>. The dispensing station includes a swivel arm member <b>104</b> and a blister seat <b>107</b>. The blister seat <b>107</b> has a concave shape which may radially match the convex shape of the blister <b>201</b>. The blister seat <b>107</b> further includes a hypodermic needle <b>112</b> which establishes a fluid passage from the blister to the vibrating aerosol generator <b>108</b>. The needle <b>112</b> has two sections. The first section <b>112</b>A extends from the dispensing seat and protrudes outwardly perpendicularly to blister seat <b>107</b>. The second end <b>112</b>B extends inwardly toward the aerosol generator <b>108</b> and is positioned in closed proximity to rear side of the vibrating membrane of aerosol generator <b>108</b>. Typically, second end <b>112</b>B will be less than 5 mm and more preferably less than 2 mm from the vibrating membrane of the aerosol generator <b>108</b>. The hypodermic needle <b>112</b> may be made of stainless steel alloy type <b>316</b> with a gage size ranging from 22 gage to 26 gage. The first section <b>112</b>A has a sharp slanted piercing tip. In use, blister <b>201</b> is placed upon the concave seat <b>107</b> and then the swivel arm <b>104</b> is rotated counter clockwise in the direction of arrow <b>115</b>.

0038Conveniently, the force upon the swivel arm <b>104</b> may be applied by a thumb against the curved portion of the arm <b>104</b>. This action forces the blister toward the piercing tip of the needle <b>112</b>A which subsequently pierces the blister <b>201</b> and squeezes its content via the needle <b>112</b> through the outlet of the needle <b>112</b>B and onto the aerosol generator <b>108</b>. When the swivel arm <b>104</b> is fully depressed, the entire dose is delivered to the vibrating membrane of the aerosol generator <b>108</b>.

0039<figref idref="DRAWINGS">FIG. 2</figref> illustrates the vibrating membrane <b>109</b> of the aerosol generator <b>108</b> in greater detail. When the content of the blister <b>201</b> is fully dispensed an indicator light <b>120</b> starts to blink signaling to the patient that the inhaler <b>100</b> is ready for use. At any time shortly thereafter the patient may inhale through the mouthpiece <b>105</b>. Patient inhalation is detected by a flow sensor which in turn activates the aerosol generator <b>108</b> to produce aerosol particles into the duct <b>111</b>. Aerosol is entrained in the inhalation air flow in the direction shown by arrows <b>121</b> and flow via the respiratory system to the lungs of the patient. When the entire dose is aerosolized, which may take one or morel breaths, the “end-of-dose” indicator light <b>121</b> lights a second time to signal the patient that the entire dose has been delivered. Delivery of the entire dose is obtained when at least about 95% of the dose is delivered, more preferably 98% and most preferably when more than 99% of the dose is delivered. In one embodiment, the opening funnel to the aerosol generator is sufficiently large such that the liquid delivery to the aerosol generator is delivered in its entirety. To receive the dose, the patient may take several inhalations or a single inhalation depending on the volume delivered to the mesh and the patient's breathing capacity. Each inhalation should be a deep breath to assure that the aerosol reaches deeply to the lungs.

0040When the end-of-dose indicator light <b>120</b> is actuated following inhalation of the contents of blister <b>201</b>, the empty blister may be removed and discarded. When the thumb pressure on the swivel arm <b>104</b> is release the blister expands to its original shape. Expansion creates a vacuum inside the blister <b>201</b> which draws back any adhered fluid from the needle back to the blister, thereby leaving the interior of the needle dry to prevent material dry-out and clogging. To further prevent possible bacterial contamination the internal and/or the external surfaces of the needle, needle <b>112</b> may be coated with silver, a silver based coating or the like.

0041<figref idref="DRAWINGS">FIG. 3</figref> illustrates the concave seat <b>107</b> of the dispensing station in greater detail. Seat <b>107</b> is provided with holes <b>117</b> which provides access to the interior of the inhaler in the vicinity of the aerosol generator <b>108</b>. This permits cleaning solvents and rinsing water to be supplied to the aerosol generator <b>108</b>.

0042<figref idref="DRAWINGS">FIG. 4</figref> provides an alternative delivery system for an inhaler <b>500</b> which utilizes a preservative free dispenser <b>550</b> and a nozzle <b>551</b> to dispense a volume of a preservative free pharmaceutical agent to the aerosol generator via an opening <b>501</b>. Inhaler <b>500</b> can be constructed in a manner similar to inhaler <b>100</b> and may include a similar aerosol generator. Opening <b>501</b> has a funnel shape which tapers down to a small opening <b>502</b>, thus forming a slope <b>503</b>. Dispenser <b>550</b> is a uniform drop, preservative free dispenser which upon activation displaces a single drop through the tip of its nozzle <b>551</b>. Preferably, the drop volume is smaller than about 200 micro-liters. A dose is dispensed by squeezing container <b>550</b> in a direction perpendicular to its longitudinal axis. Upon each actuation, a single drop of a fixed volume is displaced through the nozzle <b>551</b>.

0043One exemplary dispenser is the Aptar OSD dispenser, developed by Ing. Erich Pfeiffer GmbH. Such a container is constructed of a squeeze bottle that is squeeze to dispense a droplet. When released, the nozzle prevents microbiological contaminants from entering into the remaining liquid. This is accomplished through a tip seal (see, for example, tip seal <b>560</b> of <figref idref="DRAWINGS">FIGS. 4A and 4B</figref>) that prevents back flow of liquid into the container. As shown in <figref idref="DRAWINGS">FIG. 4A</figref>, the tip sealing mechanism includes a spring <b>562</b> that keeps the tip seal <b>560</b> in place in a normally closed position. When squeezing the bottle, liquid passes between the seal <b>560</b> and a cap until sufficient pressure is created to overcome the force of the spring <b>562</b> (see <figref idref="DRAWINGS">FIG. 4B</figref>). In this way, a single droplet can be dispensed. After dispensing, the tip seal again closes to prevent liquids from moving back into the container. To relieve the accumulating vacuum within the bottle, a small hole is included in the side of the container to allow air into the spring chamber. Droplet size can be controlled based on several factors including top size and the viscosity of the liquid.

0044In use, nozzle <b>551</b> is aligned with the opening <b>501</b> such that the drop is dispensed to the slope <b>503</b> and flows through the opening <b>502</b> to the aerosol generator. Preferably, the angle of slope <b>503</b> is greater than about 30 degrees relative to the axis of the opening <b>502</b>. The diameter of opening <b>501</b> is about 10 mm to about 15 mm and the diameter of opening <b>502</b> is at least about 5 mm. The pharmaceutical fluid in the preservative free dispenser <b>550</b> may be contained in a collapsible sack to prevent excessive agitation and which may damaged by mechanical sloshing. For example, proteins, such as insulin, may be sensitive to mechanical agitation. Use of a collapsible sack may limit undesirable agitation.

0045In another alternative embodiment, instead of using a container of the type described in <figref idref="DRAWINGS">FIG. 5</figref>, a container <b>600</b> could be used. Container <b>600</b> comprises a blister <b>602</b> manufactured using a blow-fill-seal process. Container <b>600</b> is similar to the container <b>201</b> of <figref idref="DRAWINGS">FIG. 1</figref> in that when the blister <b>602</b> is squeezed a unit dosage amount is delivered.

0046Blister <b>602</b> comprises a squeezable body <b>604</b> having a tab <b>606</b> and a twist off top <b>608</b>. Body <b>604</b> is sized to hold a unit dosage of liquid, and tab <b>66</b> may include various types of identifying information, such as the lot number, date, and the like. Twist off top <b>608</b> provides a easy way to open blister <b>602</b> so that the liquid can be dispensed.

0047Referring also to <figref idref="DRAWINGS">FIG. 6</figref>, use of blister <b>602</b> in supplying a unit dose of liquid to inhaler <b>500</b> will be described. When ready to receive a treatment, a user takes blister <b>602</b> and twists off top <b>608</b>. Typically, blister <b>602</b> will be held upright so that no liquid escapes. In some cases, the opening formed when top <b>608</b> is removed may be sized small enough to hinder liquid from escaping. Blister <b>602</b> is moved over opening <b>501</b> and body <b>604</b> is squeezed to expel the complete volume of liquid <b>610</b> into opening <b>501</b> where the liquid drains through opening <b>503</b> and to the aerosolizer. In this way, blister <b>602</b> functions as a hand squeezable, single use container for a preservative free solution. Use of a blow-fill-seal process is particularly advantageous in that the blister <b>602</b> can be manufactured at low cost while still allowing the storage of a preservative free solution. Also, the metering process is simple, requiring only the removal of the top and squeezing of the blister.

0048<figref idref="DRAWINGS">FIG. 7</figref> illustrates an embodiment of an ampoule <b>700</b> for dispensing a unit volume of a liquid to be aerosolized. Ampoule <b>700</b> comprises an elongate body <b>702</b> defining a capillary that hold a unit volume of liquid <b>704</b>. Ampoule <b>700</b> further includes a top end <b>706</b> and a bottom end <b>708</b> that may be removed from body <b>702</b>, such as by snapping them off. Body <b>702</b> may be constructed of a generally rigid material that has sufficient rigidity to permit the two ends to be easily snapped off.

0049When ready to dispense the liquid into an inhaler, top end <b>706</b> is removed as illustrated in <figref idref="DRAWINGS">FIG. 8</figref>. The surface tension in body <b>702</b> prevents leakage of any liquid <b>704</b> when ampoule <b>700</b> is inverted, such as when inserting ampoule <b>700</b> into an inhaler.

0050<figref idref="DRAWINGS">FIG. 9</figref> illustrates the ampoule of <figref idref="DRAWINGS">FIG. 8</figref> after being inserted into an inhaler <b>720</b>. Inhaler <b>720</b> may be constructed in a manner similar to the other embodiments described herein an includes electronics <b>722</b> that are employed to control operation of an aerosol generator <b>724</b> having a vibratable mesh <b>726</b>. Inhaler <b>720</b> includes an elongate opening <b>730</b> into which ampoule <b>700</b> is inserted after end <b>706</b> is removed. Once in place, end <b>708</b> is snapped off which allows liquid <b>704</b> to drain from ampoule <b>700</b> and onto the rear face of vibratable mesh <b>726</b> as illustrated in <figref idref="DRAWINGS">FIG. 9</figref>. As mesh <b>726</b> vibrates, the liquid is aerosolized and directed toward a mouthpiece <b>732</b> where the patient can inhale the medicament. Following aerosolization, ampoule <b>700</b> may be removed from inhaler <b>720</b> and discarded.

0051<figref idref="DRAWINGS">FIG. 10</figref> illustrates another embodiment of a container <b>800</b> for dispensing a unit volume of a liquid into the dispensing apparatus <b>500</b> that was previously described in connection with <figref idref="DRAWINGS">FIG. 4</figref>. Container <b>800</b> comprises a container body <b>802</b> defining a reservoir <b>804</b> for holding a volume of liquid to be dispensed. A plunger <b>806</b> is employed to force liquid in reservoir <b>804</b> through a dispensing end <b>808</b> of container <b>800</b>. Container <b>800</b> also includes a geared metering mechanism <b>812</b> that is rotated or “dialed” in order to control the extent of movement of plunger <b>806</b>. Further, an actuator <b>814</b> is pressed to move the plunger <b>806</b> by the amount permitted by metering mechanism <b>812</b>. In this way, a user can simply “dial a dose” of liquid using metering mechanism <b>812</b> and then press actuator <b>814</b> in order to dispense a metered amount of liquid into hole <b>501</b> where it will be supplied to the aerosolization mechanism.

0052Container <b>800</b> can be configured to be disposable or reusable. When reusable, reservoir <b>804</b> may comprise a cartridge that is inserted into the space defined by reservoir <b>804</b>. Exemplary volume sizes may be about 1, 1.8 or 3 ml cartridges, which may be constructed of glass, LDPE or the like.

0053The invention has now been described in detail for purposes of clarity and understanding. However, it will be appreciated that certain changes and modifications may be practiced within the scope of the appended claims.